3-Chloromethyl-4-hydroxy-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-benzo[f]indole | 198709-09-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: 3-Chloromethyl-4-hydroxy-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-benzo[f]indole
• 英文别名: [3-(chloromethyl)-4-hydroxy-2,3-dihydrobenzo[f]indol-1-yl]-(5,6,7-trimethoxy-1H-indol-2-yl)methanone
• CAS: 198709-09-0
• 化学式: C₂₅H₂₃ClN₂O₅
• 分子量: 466.921
• InChiKey: OCKXRVTVFJSRDV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.6
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  84
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  3-Chloromethyl-4-hydroxy-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-benzo[f]indole 在 1,8-二氮杂双环[5.4.0]十一碳-7-烯 作用下， 以 乙腈 为溶剂， 反应 0.5h， 生成 3-(5-Methoxy-1H-indole-2-carbonyl)-1,1a,2,3-tetrahydro-3-aza-cyclopropa[1,5]cyclopenta[1,2b]naphthalen-9-one
  参考文献：
  名称：

  Synthesis and Evaluation of CC-1065 and Duocarmycin Analogues Incorporating the Iso-CI and Iso-CBI Alkylation Subunits:  Impact of Relocation of the C-4 Carbonyl

  摘要：

  The synthesis of 2-(tert-Butyloxycarbonyl)-1, 2, 9, 9a-tetrahydrocyclopropa[c]benzo[f]indol-8-one (31, N-BOC-iso-CBI) and 1-(tert-Butyloxycarbonyl)-4-hydroxy-3-[[(methanesulfonyl)oxy]methyl]-2, 3-dihydroindole (19, seco-N-BOC-iso-CI) containing an isomeric structural modification in the CC-1065 and duocarmycin alkylation subunits and their incorporation into analogues of the natural products are detailed. The approach was based on a directed ortho metalation of an appropriately functionalized benzene (13) or naphthalene (24) precursor to regiospecifically install iodine at the C-2 position. Conversion of these respective intermediates to the dihydroindole skeleton utilized an established 5-exo-trig aryl radical cyclization onto an unactivated alkene with subsequent TEMPO trap or the more recent 5-exo-trig aryl radical cyclization onto a vinyl chloride for direct synthesis of the immediate precursors. Closure of the activated cyclopropane to complete the iso-CBI nucleus was accomplished by a selective ortho spirocyclization. The evaluation of the iso-CBI-based agents revealed a significant stability comparable to that of CC-1065 and duocarmycin A, but that it is more reactive than duocarmycin SA (6 - 7x) or the direct comparison CBI-based agents (5x) for which X-ray structure comparisons served to establish the basis for their inherent reaction regioselectivity and reactivity. Resolution and synthesis of a full set of natural product analogues and subsequent evaluation of their DNA alkylation properties revealed that the iso-CBI analogues, even with the relocation of the C-4 carbonyl and the most substantial structural modifications to the alkylation subunit to date, reacted at comparable rates and retain the identical and characteristic sequence selectivity of CC-1065 and the duocarmycins. This observation is inconsistent with the proposal that a sequence-dependent C-4 carbonyl protonation by strategically located DNA backbone phosphates controls the DNA alkylation selectivity but is consistent with the proposal that it is determined by the AT-rich noncovalent binding selectivity of the agents and the steric accessibility of the N3 alkylation site. Confirmation that the DNA alkylation reaction is derived from adenine N3 addition to the least substituted carbon of the activated cyclopropane, and its quantitation (95%) was established by isolation and characterization of the depurination adenine N3 adduct. Consistent with past studies and despite the deep-seated structural change in the alkylation subunit, the agents were found to exhibit potent cytotoxic activity that correlates with their inherent reactivity.

  DOI：

  10.1021/jo971686p
• 作为产物：
  描述：

  1-(tert-Butyloxycarbonyl)-3-(hydroxymethyl)-4-(methoxymethoxy)-2,3-dihydro-1H-benzo[f]indole 在 盐酸 、 四氯化碳 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三苯基膦 作用下， 以 二氯甲烷 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 5.5h， 生成 3-Chloromethyl-4-hydroxy-1-[(5,6,7-trimethoxyindol-2-yl)carbonyl]-2,3-dihydro-1H-benzo[f]indole
  参考文献：
  名称：

  Synthesis and Evaluation of CC-1065 and Duocarmycin Analogues Incorporating the Iso-CI and Iso-CBI Alkylation Subunits:  Impact of Relocation of the C-4 Carbonyl

  摘要：

  The synthesis of 2-(tert-Butyloxycarbonyl)-1, 2, 9, 9a-tetrahydrocyclopropa[c]benzo[f]indol-8-one (31, N-BOC-iso-CBI) and 1-(tert-Butyloxycarbonyl)-4-hydroxy-3-[[(methanesulfonyl)oxy]methyl]-2, 3-dihydroindole (19, seco-N-BOC-iso-CI) containing an isomeric structural modification in the CC-1065 and duocarmycin alkylation subunits and their incorporation into analogues of the natural products are detailed. The approach was based on a directed ortho metalation of an appropriately functionalized benzene (13) or naphthalene (24) precursor to regiospecifically install iodine at the C-2 position. Conversion of these respective intermediates to the dihydroindole skeleton utilized an established 5-exo-trig aryl radical cyclization onto an unactivated alkene with subsequent TEMPO trap or the more recent 5-exo-trig aryl radical cyclization onto a vinyl chloride for direct synthesis of the immediate precursors. Closure of the activated cyclopropane to complete the iso-CBI nucleus was accomplished by a selective ortho spirocyclization. The evaluation of the iso-CBI-based agents revealed a significant stability comparable to that of CC-1065 and duocarmycin A, but that it is more reactive than duocarmycin SA (6 - 7x) or the direct comparison CBI-based agents (5x) for which X-ray structure comparisons served to establish the basis for their inherent reaction regioselectivity and reactivity. Resolution and synthesis of a full set of natural product analogues and subsequent evaluation of their DNA alkylation properties revealed that the iso-CBI analogues, even with the relocation of the C-4 carbonyl and the most substantial structural modifications to the alkylation subunit to date, reacted at comparable rates and retain the identical and characteristic sequence selectivity of CC-1065 and the duocarmycins. This observation is inconsistent with the proposal that a sequence-dependent C-4 carbonyl protonation by strategically located DNA backbone phosphates controls the DNA alkylation selectivity but is consistent with the proposal that it is determined by the AT-rich noncovalent binding selectivity of the agents and the steric accessibility of the N3 alkylation site. Confirmation that the DNA alkylation reaction is derived from adenine N3 addition to the least substituted carbon of the activated cyclopropane, and its quantitation (95%) was established by isolation and characterization of the depurination adenine N3 adduct. Consistent with past studies and despite the deep-seated structural change in the alkylation subunit, the agents were found to exhibit potent cytotoxic activity that correlates with their inherent reactivity.

  DOI：

  10.1021/jo971686p

文献信息

• ISO-CBI and ISO-CI analogs of CC-1065 and the duocarmycins
  申请人：The Scripps Research Institute

  公开号：US06262271B1

  公开（公告）日：2001-07-17

  A series of bioactive analogs of (+)-CC-1065 (1) and the duocarmycins 2 and 3 are synthesized. The bioactive analogs include either iso-CI or iso-CBI (6 and 7) as a DNA alkylation subunit. Conjugated to the DNA alkylating subunits are a variety of DNA binding subunits. The bioactive analogs maintain their DNA selectivity and display enhanced reactivity.

  合成了一系列生物活性类似物(+)-CC-1065 (1)和duocarmycins 2和3。这些生物活性类似物包括iso-CI或iso-CBI (6和7)作为DNA烷基化亚基。与DNA烷基化亚基结合的是各种DNA结合亚基。这些生物活性类似物保持其DNA选择性并显示出增强的反应性。
• A Novel Class of CC-1065 and Duocarmycin Analogues Subject to Mitomycin-Related Reductive Activation
  作者：Dale L. Boger、Robert M. Garbaccio

  DOI：10.1021/jo991301y

  日期：1999.10.1

  alkylation sequence selectivity identical to that of the duocarmycins. Additionally, the agents exhibit a selectivity toward DT-Diaphorase (NQO1)-containing versus DT-Diaphorase-deficient (resistant) tumor cell lines, and they were shown to be effective substrates for reduction by recombinant human DT-Diaphorase. As such, the agents constitute effective duocarmycin and CC-1065 analogues subject to reductive

  描述了一种新型的DNA烷基化试剂，该试剂将丝裂霉素的醌（由于缺氧肿瘤中的优先减少和激活作用而赋予肿瘤细胞选择性）掺入了能够丝裂霉素的双霉素的AT选择性结合框架中-类似的还原活化和杜卡霉素-类似的螺环化以及随后的DNA烷基化。与该设计相一致，除非还原活化，否则醌前药不能使DNA烷基化，然后以与杜卡霉素相同的腺嘌呤N3烷基化序列选择性进行。另外，该试剂对含DT-黄递酶（NQO1）的药物相对于缺乏DT-黄递酶的（抗性）肿瘤细胞系表现出选择性，并且显示它们是通过重组人DT-黄递酶还原的有效底物。因此，这些药物构成有效的杜卡霉素和CC-1065类似物，并经过还原活化。此外，一系列反应性螺环丙烷的溶剂分解pH速率依赖性揭示了其在pH 7相对于pH 3的反应中的独特和倒序。这种行为和导致该反应的结构特征与pH 3时的酸催化反应一致，但在pH 7时直接进行未催化的S（N）2反应，该反应不会受到酸催化。
• iso-CBI and iso-CI analogs of CC-1065 duocarmycins
  申请人：The Scripps Research Institute

  公开号：US20020049335A1

  公开（公告）日：2002-04-25

  A series of bioactive analogs of (+)-CC-1065 ( 1 ) and the duocarmycins 2 and 3 are synthesized. The bioactive analogs include either iso-CI or iso-CBI ( 6 and 7 ) as a DNA alkylation subunit. Conjugated to the DNA alkylating subunits are a variety of DNA binding subunits. The bioactive analogs maintain their DNA selectivity and display enhance reactivity.

  合成了一系列活性类似物，包括(+)-CC-1065 (1)和duocarmycins2和3。这些活性类似物包括iso-CI或iso-CBI (6和7)作为DNA烷基化亚基。与DNA烷基化亚基结合的是各种DNA结合亚基。这些活性类似物保持其DNA选择性并显示增强的反应性。
• US6262271B1
  申请人：——

  公开号：US6262271B1

  公开（公告）日：2001-07-17
• US6486326B2
  申请人：——

  公开号：US6486326B2

  公开（公告）日：2002-11-26